γ-Secretase Is a Functional Component of Phagosomes

γ-Secretase is a high molecular mass protein complex that catalyzes the intramembrane cleavage of its protein substrates. Two proteins involved in phagocytosis, CD44 and the low density lipoprotein receptor-related protein, are γ-secretase substrates, suggesting that this complex might regulate some aspects of phagocytosis. Our results indicate that the four components of γ-secretase, viz. presenilin, nicastrin, APH-1, and PEN-2, are present and enriched on phagosome membranes from both murine macrophages and Drosophila S2 phagocytes. The γ-secretase components form high molecular mass complexes in lipid microdomains of the phagosome membrane with the topology expected for the functional enzyme. In contrast to the majority of the phagosome proteins studied so far, which appear to associate transiently with this organelle, γ-secretase resides on newly formed phagosomes and remains associated throughout their maturation into phagolysosomes. Finally, our results indicate that interferon-γ stimulates γ-secretase-dependent cleavages on phagosomes and that γ-secretase activity may be involved in the phagocytic response of macrophages to inflammatory cytokines. γ-Secretase is a high molecular mass protein complex that catalyzes the intramembrane cleavage of its protein substrates. Two proteins involved in phagocytosis, CD44 and the low density lipoprotein receptor-related protein, are γ-secretase substrates, suggesting that this complex might regulate some aspects of phagocytosis. Our results indicate that the four components of γ-secretase, viz. presenilin, nicastrin, APH-1, and PEN-2, are present and enriched on phagosome membranes from both murine macrophages and Drosophila S2 phagocytes. The γ-secretase components form high molecular mass complexes in lipid microdomains of the phagosome membrane with the topology expected for the functional enzyme. In contrast to the majority of the phagosome proteins studied so far, which appear to associate transiently with this organelle, γ-secretase resides on newly formed phagosomes and remains associated throughout their maturation into phagolysosomes. Finally, our results indicate that interferon-γ stimulates γ-secretase-dependent cleavages on phagosomes and that γ-secretase activity may be involved in the phagocytic response of macrophages to inflammatory cytokines. γ-Secretase catalyzes the cleavage of selected type I transmembrane protein substrates within their membrane-spanning domains, an atypical hydrolytic event considering that it occurs in the hydrophobic conditions of the lipid bilayer (1Xia W. Wolfe M.S. J. Cell Sci. 2003; 116: 2839-2844Crossref PubMed Scopus (78) Google Scholar). This type of intramembrane proteolysis was discovered as an essential step in the release of β-amyloid peptides from the amyloid precursor protein (APP), 3The abbreviations used are:APPamyloid precursor proteinLRPlow density lipoprotein receptor-related proteinPSpresenilinNTFN-terminal fragmentCTFC-terminal fragmentpAbspolyclonal antibodiesIFN-γinterferon-γTNF-αtumor necrosis factor-αDAPTN-(N-(3,5-difluorophenacetyl-l-alanyl))-S-phenylglycine t-butyl esterPBSphosphate-buffered salineCHAPS3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acidBNBlue nativeTricineN-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycineCHAPSO3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonic acid 3The abbreviations used are:APPamyloid precursor proteinLRPlow density lipoprotein receptor-related proteinPSpresenilinNTFN-terminal fragmentCTFC-terminal fragmentpAbspolyclonal antibodiesIFN-γinterferon-γTNF-αtumor necrosis factor-αDAPTN-(N-(3,5-difluorophenacetyl-l-alanyl))-S-phenylglycine t-butyl esterPBSphosphate-buffered salineCHAPS3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acidBNBlue nativeTricineN-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycineCHAPSO3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonic acid a pivotal process in the development of Alzheimer disease pathology (2Selkoe D. Kopan R. Ann. Rev. Neurosci. 2003; 26: 565-597Crossref PubMed Scopus (560) Google Scholar). γ-Secretase activity was later found to function in Notch signaling by releasing the Notch intracellular domain, which translocates to the nucleus and activates the transcription of target genes (2Selkoe D. Kopan R. Ann. Rev. Neurosci. 2003; 26: 565-597Crossref PubMed Scopus (560) Google Scholar). Several other γ-secretase substrates, including CD44, Notch ligands, and the low density lipoprotein receptor-related protein (LRP; also known as CD91), have been identified, and all share a common type I transmembrane protein topology (3Koo E.H. Kopan R. Nat. Med. 2004; 10: S26-S33Crossref PubMed Scopus (151) Google Scholar). γ-Secretase cleavage of these substrates is preceded by proteolysis within their extracellular domains (3Koo E.H. Kopan R. Nat. Med. 2004; 10: S26-S33Crossref PubMed Scopus (151) Google Scholar). Although the biological function of γ-secretase cleavage remains to be deciphered for many substrates, recent evidence indicates that the role of γ-secretase in signal transduction may not be limited to the Notch pathway. Other γ-secretase substrates, including APP, CD44, and LRP, have indeed been shown to generate transcriptionally active C-terminal fragments (4Cao X. Südhof T.C. J. Biol. Chem. 2004; 279: 24609-24611Google Scholar, 5Lammich S. Okochi M. Takeda M. Kaether C. Capell A. Zimmer A.K. Edbauer D. Walter J. Steiner H. Haass C. J. Biol. Chem. 2002; 277: 44754-44759Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar, 6May P. Reddy Y.K. Herz J. J. Biol. Chem. 2002; 277: 18736-18743Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar). Conversely, cleavage by γ-secretase terminates intracellular signaling mediated by the netrin receptor DCC (deleted in colorectal cancer) (7Parent A.T. Barnes N.Y. Taniguchi Y. Thinakaran G. Sisodia S.S. J. Neurosci. 2005; 25: 1540-1549Crossref PubMed Scopus (58) Google Scholar). Taken together, these studies suggest that γ-secretase-mediated cleavage may be generally involved in cell signaling. amyloid precursor protein low density lipoprotein receptor-related protein presenilin N-terminal fragment C-terminal fragment polyclonal antibodies interferon-γ tumor necrosis factor-α N-(N-(3,5-difluorophenacetyl-l-alanyl))-S-phenylglycine t-butyl ester phosphate-buffered saline 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid Blue native N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonic acid amyloid precursor protein low density lipoprotein receptor-related protein presenilin N-terminal fragment C-terminal fragment polyclonal antibodies interferon-γ tumor necrosis factor-α N-(N-(3,5-difluorophenacetyl-l-alanyl))-S-phenylglycine t-butyl ester phosphate-buffered saline 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid Blue native N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonic acid Significant research efforts have recently been invested in characterizing the biochemistry of γ-secretase. Cumulative evidence indicates that γ-secretase consists of a high molecular mass complex composed of at least four different proteins, viz. presenilin (PS)-1 or the less abundant homolog PS2, nicastrin, APH-1, and PEN-2, all of which are integral membrane proteins (8Iwatsubo T. Curr. Opin. Neurobiol. 2004; 14: 379-383Crossref PubMed Scopus (152) Google Scholar). Current models propose that PS1 contains the catalytic site of γ-secretase, an unusual aspartyl protease with two aspartates located in transmembrane domains 6 and 7 of PS1, respectively (9Wolfe M.S. Xia W. Ostaszewski B.L. Diehl T.S. Kimberly W.T. Selkoe D.J. Nature. 1999; 398: 513-517Crossref PubMed Scopus (1685) Google Scholar). Nicastrin and APH-1 are suggested to function in stabilizing and trafficking full-length PS1 through the secretory pathway (10LaVoie M.J. Fraering P.C. Ostaszewski B.L. Ye W. Kimberly W.T. Wolfe M.S. Selkoe D.J. J. Biol. Chem. 2003; 278: 37213-37222Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar). PS1 undergoes endoproteolysis in its cytoplasmic loop, located between transmembrane domains 6 and 7, generating the N-terminal (NTF) and C-terminal (CTF) fragments, which remain associated in the complex (11Thinakaran G. Borchelt D.R. Lee M.K. Slunt H.H. Spitzer L. Kim G. Rotovitsky T. Davenport F. Nordstedt C. Seeger M. Hardy J. Levey A.I. Gandy S.E. Jenkins N.A. Copeland N.G. Price D.L. Sisodia S.S. Neuron. 1996; 17: 181-190Abstract Full Text Full Text PDF PubMed Scopus (939) Google Scholar, 12Capell A. Grunberg J. Pesold B. Diehlmann A. Citron M. Nixon R. Beyreuther K. Selkoe D.J. Haass C. J. Biol. Chem. 1998; 273: 3205-3211Abstract Full Text Full Text PDF PubMed Scopus (298) Google Scholar). PEN-2 apparently promotes this cleavage event, a key step in the activation of γ-secretase (13Takasugi N. Tomita T. Hayashi I. Tsuruoka M. Niimura M. Takahashi Y. Thinakaran G. Iwatsubo T. Nature. 2003; 422: 438-441Crossref PubMed Scopus (783) Google Scholar). Several reports have demonstrated that the coexpression of all four proteins is required to produce functional γ-secretase (13Takasugi N. Tomita T. Hayashi I. Tsuruoka M. Niimura M. Takahashi Y. Thinakaran G. Iwatsubo T. Nature. 2003; 422: 438-441Crossref PubMed Scopus (783) Google Scholar, 14Kimberly W.T. LaVoie M.J. Ostaszewski B.L. Ye W. Wolfe M.S. Selkoe D.J. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 6382-6387Crossref PubMed Scopus (676) Google Scholar, 15Edbauer D. Winkler E. Regula J.T. Pesold B. Steiner H. Haass C. Nat. Cell Biol. 2003; 5: 486-488Crossref PubMed Scopus (775) Google Scholar, 16Hu Y. Fortini M.E. J. Cell Biol. 2003; PubMed Scopus Google Scholar, T. C. Sisodia S.S. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). Although the of a functional γ-secretase complex in the Sisodia S.S. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google γ-secretase its substrates in of the secretory pathway and in of the pathway M. S. D.J. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, N. E. F. P. A. A. C. J. Cell Biol. 2004; PubMed Scopus Google Scholar). remains γ-secretase cleavage at the that the of Notch recently been as a for its by γ-secretase N. E. F. P. A. A. C. J. Cell Biol. 2004; PubMed Scopus Google Scholar). is a process used by a of from to to the of or A. Rev. 2002; PubMed Scopus Google Scholar). formed phagosomes in a maturation process that with of and with The of in as macrophages the of in the phagosome protein which are at the cell to and are in the least two substrates of γ-secretase, CD44 and known as (3Koo E.H. Kopan R. Nat. Med. 2004; 10: S26-S33Crossref PubMed Scopus (151) Google are involved in and are known of phagosome membranes S. M. R. T. J. 2003; PubMed Scopus Google Scholar, A. D. B. J. Med. PubMed Scopus Google Scholar). to the γ-secretase complex to phagosomes and γ-secretase cleavage on this In this that all of the components of the γ-secretase on phagosomes of both murine macrophages and Drosophila phagocytic The of γ-secretase on phagosomes that γ-secretase with lipid on phagosome is present as a high molecular mass complex of and catalyzes cleavages on Our results that the γ-secretase complex is an and of suggesting that γ-secretase some of the of this was from the The and polyclonal antibodies and the from The the and from The and and of PS1 (11Thinakaran G. Borchelt D.R. Lee M.K. Slunt H.H. Spitzer L. Kim G. Rotovitsky T. Davenport F. Nordstedt C. Seeger M. Hardy J. Levey A.I. Gandy S.E. Jenkins N.A. Copeland N.G. Price D.L. Sisodia S.S. Neuron. 1996; 17: 181-190Abstract Full Text Full Text PDF PubMed Scopus (939) Google Scholar, G. Price D.L. Borchelt D.R. Sisodia S.S. Neurobiol. 1998; M. PubMed Scopus Google Scholar). The was of S. P. D. M. H. Thinakaran G. J. 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PS1, PS2, nicastrin, and APH-1 the of these the of γ-secretase components in phagosomes with a cell and a cell membrane was demonstrated in PS1, nicastrin, and PEN-2 enriched on phagosome The PS1 and the of PS1 with full-length PS1 that the form of PS1 to the of that was present in its form The in molecular mass with is expected of proteins as A. F. G. H. S. H. M. Nixon Gandy S.E. P. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). The PS1 on phagosomes was present in to a form of the PS1 and a of PS1 cleavage by Tomita T. S. Takahashi M. T. E.H. Iwatsubo T. Thinakaran G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Nicastrin and PS1 also by of phagosomes In contrast to the of the phagosome PS1 and was in on phagosomes a that may the of γ-secretase components with lipid microdomains of the γ-secretase protein complex on the phagosomes of murine macrophages and Drosophila S2 by S2 in a the γ-secretase cleavage of on the of the C-terminal fragment of LRP, a of γ-secretase and of the γ-secretase components was in macrophages with for to phagosome phagosomes and of phagosomes from or in was for the The cleavage of the PS1 by is by the in the or of a to the of for and phagosome of phagosomes and the PS1 was by The cleavage of the PS1 by is by the components are associated with phagosome lipid phagosomes from in or the of the membranes on an from the of the from in and was for the and are shown as a for and proteins, γ-Secretase components are proteins from to (1Xia W. Wolfe M.S. J. 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Full Text Full Text PDF PubMed Scopus Google was phagosomes at γ-Secretase activity was also on phagosomes a was to with of and this activity was by the γ-secretase phagosomes also a in activity with cell membranes with the of γ-secretase on results of substrates occurs on this key in in the of and the of protein A. Rev. 2002; PubMed Scopus Google Scholar). are by as an inflammatory that stimulates the activity of and the of at the cell K. T. J. Biol. 2004; PubMed Scopus Google Scholar). inflammatory have recently been shown to γ-secretase activity Wolfe M.S. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google the activity of this complex on macrophages with to phagosome and the of a cleavage on the of LRP, was P. H.H. J. Herz J. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). shown in the of by γ-secretase was the of the γ-secretase components on that phagosomes from a in the of the PS1 which to the cleavage of the PS1 by Tomita T. 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The of γ-secretase substrates recently the of two known components of CD44 and the that these and other to be γ-secretase substrates be on to γ-secretase activity is associated with In this have demonstrated that γ-secretase is a and of to essential phagosomes a for γ-secretase in as the of γ-secretase was found to be with that of the γ-secretase components found to be enriched on Drosophila suggesting for γ-secretase on this the of γ-secretase with phagosomes indicate that the of γ-secretase remains throughout Our results indicate that γ-secretase components the of the active as the of high molecular mass complexes and the with lipid Finally, phagosomes shown to γ-secretase of recent studies have on characterizing the complexes of molecular formed by the γ-secretase In with our reports have demonstrated an abundant complex of C. Kim T. H. L. R. Sisodia S.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D. Winkler E. Haass C. Steiner H. Proc. Natl. Acad. Sci. U. 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Chem. 2002; 277: 44754-44759Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar). γ-secretase activity may be involved in the different that are of at the of phagocytic recently been shown to the of inflammatory of M. D.R. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). γ-secretase been to many intracellular M. S. D.J. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, S.E. A. B. J. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, S. C. S.E. A. B. J. M. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google it is that substrates of γ-secretase Our the that γ-secretase cleavage may to phagosome In with this our results that the γ-secretase cleavage of on In our indicate that γ-secretase is for the phagocytic response of macrophages to and suggesting that γ-secretase cleavage are of the pathway by inflammatory cytokines. studies the role that γ-secretase substrates in this for and all the of the for

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